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Host-Switching Mutations in H5 Hemagglutinin Suppress Protein Dynamics at Activation pH

ABSTRACT: Increase in the occurrence and severity of human H5N1 spillover infections resulting from dissemination of highly pathogenic avian influenza (HPAI) virus into bird and mammal populations raises concerns about HPAI adapting to become human transmissible. Studies identified hemagglutinin acid stability and receptor preference as essential molecular traits that shape host tropism. Mutations that increase hemagglutinin acid-stability and affinity for a-2,6-linked sialic acids have been shown to confer H5N1 airborne transmissibility in a ferret model. Here, we use hydrogen/deuterium-exchange mass spectrometry to dissect how airborne adaptation mutations impact dynamics during activation. Our results reveal that such mutations suppress dynamics in pH-responsive regions including the fusion peptide and receptor binding and fusion subunit interface, which would prevent premature inactivation during airborne transmission. These results for HPAI hemagglutinin identify regions that are hotspots for adaptive changes and reveal general influenza subtype-specific patterns.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sally Kephart

LAB HEAD: Kelly K. Lee

PROVIDER: PXD059353 | Pride | 2025-10-30

REPOSITORIES: Pride

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			Action	DRS
	ByonicFiles.zip	Other
	Colo22_pH5p8.zip	Other
	Colo22_pH7p4.zip	Other
	Indo05_Mutant_pH5p8.zip	Other
	Indo05_Mutant_pH6p1.zip	Other

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